Note: Descriptions are shown in the official language in which they were submitted.
,.
1340fi95
_2-
US Patent 4,341,784 discloses certain substituted
7-(3-amino-1~-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-
dihydro-4roxo-1,8-naphthyridine-3-carboxylic acids
having the general formula:
S
F ~ ~ ~ C02H
N
. I
C2H5
NHR
The compounds are disclosed to have antibacterial
activity.
The Journal of Medicinal Chemistry, 23, 1358
(1980) discloses certain substituted quinoline-3
carboxylic acids having the structural forauula
F ~ ~ ~ C02H
N
1
C2H5
wherein- may be pyrrolidinyl. See also US Patent
4,140,719. The compounds are disclosed to have anti-
bacterial aci:ivity.
European Patent Application 81 10 6747,
Publication Number 047,005, published March 10, 1982,
discloses certain benzoxazine derivatives having the
structural formula
A / C02H
I i
i~
''y,~ R
r
13~:os9~
-3-
wherein A is halogen and B may be a cyclic amine
substituent such as pyrrolidine, or piperidine.
Certain 7-heterocyclic substituted 1,8-
naphthyridines are disclosed in Eur. J. Med) Chem. -
S Chimica Therapeutica, 29, 27 (1977) . tiS Patents
3,73,993 and 3,907,808 disclose certain 7-pyridyl-
quinolines.
Japanese Patent Publication Number 109,181,
published December 27, 1983, describes pyrido (1,2,3-
de)(1,4)benz~oxazine-6-carboxylic acid derivatives. _
The references teach that these compounds possess
antibacterial activity.
The invention in a first generic chemical
compound aspect is a compoLend ha«ing the structural
1 S formula I or Ia
Y O y
s ai
~3C02R1 F' / C02R1
or
xN 2 Z ~ N
s I
R2 W _
R4
Ia
wherein Z is
R-~1 ~ l~f- , R-N ~ N , R-N N-
/ r R_N~N-
R' HT! ~ H
N- . ~ ~ N-, or ~4 N-
H '~ ~~ R' HN ~ ~ '~ i
a
i34069a
in which R is hyd::o5en, aik~~l of one to three caraun
atoTS, hydroxlalkyl of twc ';r tzree carbon atoms,
benzyl or i-a;ainobenzyl; R' is hydrogen or alkanoyl
O~ ~~J!i~ onar Z:J ~r:Y'~?t'. C3'L'bGn a~~alSi X i3 C11, i.~', Or
N; '~ is hj~drcgen, fi~:oro, or aunino; W is O, Hit, 5 or
CH; R1 is hydrogen., alkyl having from one to six
carbon atoms or a cation; R2 is alkyl having from onQ
to four carbon atons, vinyl, haloalkyl, or
hydroxyaikyl having from two to four carbon atoms, o;
1G cycloalk~rl having three to six carbon atoms; R3 is
hydrogen or alkyl having from one to th=~e carbon
atoms; R,~ is hydrogen or alkyl from one to three
carbon atoms, and the pharmacerlticaliy acceptable acid
adaici~n or base salts thereof.
Preferred compounds of this invecltion ars t:~ose
wherein Y is hydrc:ge:~.
Preferred 1:9i~pUllft~Is of t~:is invention are also
those of formu'a Z wnerair, X is N, or C-e.
Other preferred compounds o' this nv~-~tyon are
thoae of formula Ia wherein and n; and R.~ are earn
hydrogen or .~.rethyl.
Other preferred colnpor:nds of this invention aru
t::ose wherein R1 is hydrogen or a pharmaceutically
accep;.able base salt such as a me tal or arrive sa? =.
Other przferred ccmpeunds .~f tnis in.-snt~cn are
those wherein R2 is ethyl, vinyl, 1-fluoroet_n::l or
cyc:~~~pr_opj,l ,
?articuiarly preferred species of the in«entior
arA the compcunc~s ha~.ring the names:
xU 7-~2,5-aia~a~~i~:ycloi2.2.2joct-2-yl)-1-etayl-5,8-
aivluor~~-1, "*~-dihydro-4-«xo-3-quinolinec~3rboxylic aci.l;
7-( 2, 5-dia~a;~~cyc to ( ~. 2, 'd j oct-2-y i )-1-Athyl-6-fir~::~r~-
1, ~-dii~=dro-4-oxo-I, S- naphth;~ridi!~e-~-carboxylic
ac_.;~;
~7 !-i yr :-'~idv3~~.L::'sC' u.''.) ~~~ > ~. ZjCiCrwt~.'~~s' !-1-
<~i,:l~7L::~C~nvj.'t:,
3 -~~:i 1: j .1 t~ i O- i ~ ~ -!7 ~. ,1';~ ~ 't :J- ''i -!: .~. ~ - ,% -' ~
'..11'1 C~ J. 1 !7 ;~ t.:a ~ !.''. C ia'1! ~ 1 ~::
~.:l~.i;
.,
. , 134069
-5_
7-( 2, 5-diazab icycl.o [ 2. 2. 2 J oc t-2-yl ) -1-cyclopropyl-6-
fluoro-1,4-dihydra-4-oxo-1,8-naphthyridine-3-
carboxyl is a.c id ;
7-[3-( exo-amino) -8-azabicyclo[ 3. 2: lj oct-8-yl j -1-
ethyl-6, 8-difluora-1, 4-dihydro-4-oxo-3-quinoline-
carboxylic acid;
7- [3-( exo-amino) -8-azab icyclo [ 3 . 2.1 J act-8-yl ] -I-
ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-
3 -carboxyl is ac id ;
7-[3-(exo-amino)-8-azabicyclo[3.2.1Joct-8 y1J-1-
cyclopropyl-6, 8-di.fluoro-1, 4-dihydro-4roxo-3-quinol ine-
carboxylic acid;
7-[3-(exo-amino)-8-azabicyclo[3. 2. 1J oct-8-yl] -I-
cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid;
7-(1, 4-diazabicyclo[3. 2. 1] oct-4-yl )-1-ethyl-6, 8-
d ifluoro-l, 4-dihyd ro-4-oxo-3-qu inol inecarboxyl is ac id;
7-(1,4-diazabicyclo[3.2.1]oct-4-yl)-1-ethyl-6-fluoro-
l, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid;
7-(1,4-diazabicyclo[3.2.1]oct-4-yl~-1-cyclopropyl-6,8-
difluoro-1,4-dihydro-4-oxo-3~uinolinecarboxylic acid;
7-( Z, 4-diaza,b icyla [ 8 . 2.1 J oc t-4-yl ) -1-cyclopropyl-6-
f luoro-l, 4-dihydra-4-oxo-1, 8-naphthyr id ine-3-carboxyl is
ac id;
7-[3-endo-amino-8-azabicyclo(3.2.1)act-8 ylJ-1-ethyl-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxyi is acid;
7-[3-endo-amino-8-azat~icyclo( 3. 2. 1 )oct-8-yl j -1-ethyl-
6, 8-difluoro-1, 4-dii~yd ro-4-oxo-3-~uinolinecarboxyl is
3 0 ac id ;
7- [3 -endo-am ino-8-azab icyclo( 3 . 2. ~ ) vc t-8-y1 j -i-cyc 30-
propyl-5-fluaro-l, 4-dihydro-4-oxo-1, 8-naphthyridine-
3 -carboxyl is ac id ;
7-[3-exo-amino-8-azabicyclo( 3. 2. 1)oct-8-ylj -1-cyclo-
propyl-5-fiuoro-1, ~-dihydro-4-oxo-1, 8-naphthyridine-
3 -carboxyl is ac id ;
. , ,
-6-
1-cyclopropyl-6-fLuoro-1, 4-dihydro-7-(5-met~yl-2, 5-
d iazab icyclo~ [ 2. 2. 2] oc t-2-yl ) -1, 8-naphthyr id ine-3-
carboxylic acid;
1-cyclopropyl-6-fLuoro-1, 4-dihydro-7-(5-methyl-2, 5-
d iazab icyclo ( Z. 2. 1] kept-2-yl ) -4roxo-1, 8-naphthyr id ine-
3-carboxyl is ac id; '
1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-7-(5-methyl-
2, 5-diazabicyclo[2,. 2. lj hept-2-yl )-4-oxo-3-quinaline-
c arboxyl is ac id ;
7-[2,5-diazabicycl.o(2.2.1)hept-2-ylj-1-ethyl-6,8-
c~ifluoro-1, 4-dihydro-4roxo-3-quinolinecarboxyiic
acid:
7-(2, 5-diazabicyclo( 2. 2. 1)hept-2-yl] -1-ethyl-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid:
1-cyclopropyl-7-[2,5-diazabicyclo(2.2.1)hept-2 yy]-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid;
1-cyclopropyl-7-[2, 5-diazabicyclo( 2. 2. 1)hept-2 yl] -
6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
ac id;
10-(2, 5-diazabicyclo( 2. 2. 1)hept-2 yl] -9-fluoro-2, 3-
dihydro-3-methyl-7-oxo-7H-pyrido( l, 2, 3-de)-I, 4-
benzoxazine-6-carboxylic acid;
1-ethyl-6, 8-difluoro-1, 4-dihydro-4-oxo-'-[S-(phenyl-
methyl )-2, 5-diazabicyclo( 2. 2. 1)hept-2-y.Lj -3-
qu inol inecarboxyl is ac id;
10-(2,5-diaz.abicy~lo(2. ~.?.]pct-2-yl)-9-fluoro-2,3-
d ihyd ro-3-me thyl- % -~::ca-"~i-ovr ida ~ 1 ~ 2, 3-de] -l, 4-
3 0 benzoxazine-6-carboxyl is ac id;
I-cyclopropy.L-e-fluoro-1, 4-dihydro-7-[5-(2-hydroxy-
e thyl ) -2, 5-d is zub icvc l o ( 2 . 2. 2 ) oc t-2-yl ] -4-oxo-1, 8-
naphthyridine-3-carboxyl is acid,
and the pharmaceutically acceptable acid addition or
3 S base sal is theL eof .
-- ~ ~34os9~
_,_
The invention includes a process for preparing
compounds of the formula
Y O
F. / ~ ~ C02R1
or 2R1
Z~ ~X ~N
I
R2
R3
Ia
wherein Rl, Ft2, R3, R4, W, X, Y, and Z are as
S def fined ~ for formulae I and Ia which comprises reacting
a compound having the following structural formula
Y
F. / ~ ~02R1. 2R1
a ~I or
L~ \ X
~2
R3
I V'
~34069~
_g_
with an amine corresponding to the group Z wherein Z
is a compound having the structural formula
R-N ~ H , R-N- r -NH , R-N NH
R-N~NH ,
VI VIa VIb VIc
R' HN ~~ H ~
NH , . NH or t/ \NH
lii~ ' ~ R' HN
VId VIe VIf
wherein all of the above terms are as defined in
formulae I and Ia and L is a leaving group which is
halogen or an alkylsulfonyl group of from one to three
carbon atoms, preferably fluorine, chlorine, m~ethane-
or ethanesulfonyl.
The invention also includes a pharmaceutical
composition which comprises an antibacterially
effective amount of a compound having structural
formula I or Ia and the pharmaceutically acceptable
salts thereof in combination with a pharmaceutically
acceptable carrier.
The invention further incluues a method for
treating bacterial infections in a mammal whic:~
comprises administering an antibacterially effective
amount of the above defined pharmaceutical composition
to a mammal in need thereof.
-9-
The compounds of the invention having the
structural formulae III and IIIa may be readily
prepared by treating a corresponding compound having
the structural formula IV or V with the desired cyclic
amine VI-f. Eor purposes of this reaction, the
. alkylamine substituent of compounds VI-f may, if
desired, be protected by a group ~ahich renders it
substantially inert to the reaction conditions. Thus,
for example, protecting groups such as the following
may be utili::ed: carboxylic aryl groups such as
formyl, acetyl, tr:ifluoroacetyl; alkoxycarbonyl groups
such as ethoxycarbonyl, t-butoxycarbonyl, B,B,~-
trichloroethoxycarbanyl, S-iodoethoxycarbonyl;
aryloxycsrbonyl groups such as ~enzyloxycarbonyl,
E-methoxybenzyloxycarbonyl, phenoxycarbonyl; silyl
groups such trimethylsilyl; and groups such as trityl,
tetrahydropyi:anyl, vinyloxycarbonyl, o-nitrophenyl-
sulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and
benzyl, may all be utilized. The protecting group may
be removed, after the reaction between compound IV or
V and compounds VI~-f, if desired, by procedures known
to those skilled in the art. For example, the ethoxy-
carbonyl group may be removed by acid or base
hydrolysis and the trityl group may be removed by
hydrogenolys:is.
1344695
-10-
The reaction between the compound of structural
formula IV or V and a suitably protected compound cf
formula VI-f may b~e performed with or without a
solvent, preferably at elevated temperature for a
sufficient tame so that the reaction is substantially
complete. The reaction is preferably carried out in
the presence of an acid acceptor such as an alkali
metal or alkaline earth metal carbonate or
bicarbonate, a tertiary amine such as triethylamine,
1,8-diazabicyclol5.4,0]undec-7-ene (DBU), pyridine, or
picoline. A:Lternatively an excess of a compound of
formula VI-f may be utilized as the acid acceptor.
Convenient solvents for this reaction are non-
reactive solvents such as acetonitrile, tetra-
hydrofuran, ethanol, chloroform, dimethylsulfoxide,
dimethylformamide, pyridine, picoline, water, and the
like. Solvent mixtures may also be utilized.
Convenient reaction temperatures are in the range
of from abou t 20° to about 150°C; higher temperatures
usually require shorter reaction times.
The removal of the protecting group may be
accomplished either before or after isolating the
product, III or IIIa. Alternatively, the protecting
group need not be removed.
The starting compounds having structural formulae
IV and V are known in the art or, if new, ray be
prepared from known starting materials by standard
procedures or by variations thereof. Thus the
following compounds are disclosed in the noted
references:
~3446~~
_11_
C02ii
C2H~
O
,1
F
i
cl ~ N u.J
European Patent Publication 27,752 of April 29, 1981
F r02H
~1
f:ed. Chew. , 23, I35$ (i98~? j
0
F ~/~~ ~ :-0 '~i
~J
C 1 ~~:: ~~~~1-'
i
Europea n patent Publication Jt~783F2 of May 11, 1983
0
i .- .~..!~1
H
1 l) If ..'
i i ii
i
F. ~~/~/~...I3'' -
C..H_
G 'J
E;zronear. Patant 0 ~~?i~ 203 (1979)
~..~~.f..,:..
;i
;;
L ~~
W ,.:
c
J ~ ~'
3r'~~.:~~: : :~~~:~ ." i'w~~,=a~; of April 1, 1981
~~~~695
.,
~'i.L~
CC2H F ~~~C02ii
Ii !j
F ~' N ~
1 i
3
Japar.~es2 Patent European Pa ~~rt
Publication Publication
7203-085 of December 13, 1982 47,005 of March 10, 1982
rz~: ~ o
F C2~! F~~ ~~~ CC2H
j.
F cW~~~~-~
E4
Japa~:ese Patent ~iaparese Patea
P~,:bl.~ca tian P~abli:: 3 t=o:~
720.~~-085 of December 13, 1982 81 ~'~ 35%'"'~ of October 13,
1983
NH2 O
t ;fit i
i i j I
0~~~,%~CH .~ '-~./~vii 3
,~ana:.ese F~at~r.~~ ~?ritis~! P~~tant
Pub'_icaLic~:~ 2,057,440 of
~ a9-?go of September 14, 1982 April 1, 1981
4
r
~34069y
-13-
1-Cyclo,Propyl-6, 7, 8-trifluoro-1, 4-dihydro-4-
oxo-3-qu inol inecarboxyl is ac id may be prepared by a
series of reactions starting from 2, 3, 4, 5-tetrafluoro-
benzoic acid. The sodium salt of 2, 3, 4, 5-tetrafluoro-
benzoic acid is reacted with oxalyl chloride and the
produc t condensed wi th d ie thyl malonate in the
presence of magnesium turnings to afford after
hydrolysis 2, 3, 4, 5-tetrafluorobenzoylacetic acid,
ethyl ester. This compound is, in turn, treated with
triethylorthoformate and acetic anhydride, followed by
cyclopropyl amine to of ford 2-( 2, 3, 4, 5-tetrafluoro-
benzoyl ) -2-c;tclopropyl aminoacryl is ac id, ethyl ester,
which is then ring closed and hydrolysed with sodium
hydride to give the desired intermediate.
7-Chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-
oxo-l, 8-naphi~hyrid ine-3-carboxyl is ac id may be pre-
pared by a series of reactions starting fror~n 4-(6-
chloro-3-niti:o-2-pyr id inyl ) -1-piperazinecarboxyl is
acid, ethyl Eater. The intennediate, 1-cyclopropyl-
2 0 6-fluoro-1, 4--d ihyd ro-4-oxo-7-( 1-piperazinyl ) -1, 8-
naphthyridinE:-3-carboxyl is acid can be converted to
the 7-hydroxy derivative with a mixture of nitric and
sulfuric acids which is then replaced by crilorine by
treatment with phosphorus oxychloride to give the
desired intezvmediate. The synthesis of bot,.~ of the
above N-cyclopropyl intermediates is described in the
Preparative Examples.
The comFr~urds of the invention having structural
rorn:ula VI-f, are either known compounds or they may
see prepared from known starting materials by standard
procedures or by variations thereof . For example,
exo and endo 3-amino-8-azabicyclo 13.2.1j octaves
having the structural formula B and the acetyl
derivatives E:
_ X340695
-1~-
H~~N_.g H ,~ N-H
H2N ~_i' '~ AcHN ~s'
g E
may be readily prepared from the kncwn starting
material 8-(phenylmethyl)-8-azabicyclo[3.2.1]octan-3-
one oxime, (~1. R. l3agley and T. N. Riley, J. Hetero-
cyclic Chem." 19, 485 (1982)] by the following
reaction sequence.
H~'\
HON ~~ -CH2 '~ H2~ ~N-H
vrr
H ~~ H
NCH~~ ~~'NCH2~
r'w ~!~/ AcHN .s' '
D
H~ ~ ~\
AcHN s'''' N-H
E
The ccmx~ounds of the invention display anti-
bacterial ac~:ivity when tested by the microticra~:iors
dilution met'aoc? as described ir) Heifstz, et al,
Anti;nicr. Agents & Ghemoth . , ~; i24 ( 1.97 ~.
By use c>f the above referenced methof:, t:ze
fol lowed "ii n .m:im inhibitory co:~c.~ntration values (:~i_TCs
n ~g/m' ? ::r~_;~an in the table were obtaine-.~ for
reprnsen~:~tiv~e ~~ompounc~s of t:~e invEr.tion.
1340695
-15-
=o
r-i J' ~ t0 t0 ~ N LO ~D ~D
O .
Cr ~ O O O .-i r'1 O O .-f ~-1 r-t
Ex v
3"
c~ m
.-1O r'Ir-1 CO N C9 lp N
N
O , . . . . . . .
.
c~.,o c~ 0 0 0 0 0 0 ~ o
x
~w
'O
U
I
O r1 O N r-i CO N OCR Q"J
N
. . . . . . . . . .
p
,x o c~ 0 0 0 0 0 0 0 0
~w
i~
_ _~. _ __ ___ _ ---- __,__
O
Ea-~ 'C -
ro
H iJ y0 t0
i0 ~ tf1 tn O
N ~ Q rl-1 O C~ N O O C~ V~ er
.
H ~ ~ .
k
~ O O O O O O O O O O
W
U
a c
_-
x E .v
w c 'n
~
Sr ~ SC1u~ N
U O o a -i a~ ao ~w o vo ~ o
~,x
f!7 (~ O O O O O O O .-t .-iO
W
'
~
C .~___ ~- _ _..~--._-- _- _.
H) i
O 'D
fY.-1 C
N'
[iof ~ N ~I ~ O d~ ~ ,-1t0 b
N ~ p . . . . . . . .
.I
> .~ :.x~, o c: o o o o o ~ o o
C ~
wi
3I
N
-
O N 1 ~"7
N .-~10~ V 1 O
to I 1 N (~ x N
N x t-! N 1 Ci i
U O V ~ 'V V
r1 x '.~ (~1
ro ,n ..~~r
(D U ~ N C? to ~' C
y tr 'a -~ o ~ ~ r~ o c
C U :> C ~ '~' Sr 1) U
U7 t:s O ~ ~ 3 U U p
...' O ..r ..r' R1 t0 ~0 C ?r
L', r-1ri '~ 1.1~.1 W ~ Qy
O ~.~C~ a~ n ~n
a, ;) O :",~t U U s? cn m
S.r 1.t Qr r.~ U U ~ U ?
0 ~U'0 ~ 'n U U U U U
~~ rt3c:)!t1 O O U U U
U y. --~S..a.~. U U O O C
i '~!) ~ O O O :7 :1 U
S)i J :C .-I..~O O O
i ~_S~ .-~= O ?~ ~.,y i..r
S.J:;) UT 'D ''3 .L~'" W Oa '_~,y
r~ y "J ~~ ~ri.~..1
a-~c) Q! O s3 :0 ~ 1.' S..1.:
''
C tn r~ ~.1rn ~.71J JJ t~ 11
w w :~ o. w 'n cn cn ~n cn
1340fii95
CO
;~ d ~ ~1'd d d~ N d C
N
Q
- Q,, O C7 O O O O O J O O
.
~
x
w
._i . . - _ _ _- _
3 __ _
~;
~ m ~n
.-r
O N tY1 ~ N
~
O O O O N er sr O N ~ .-1
.I
cza
x
~w o c, 0 0 0 0 0 0 0 0
>~
~
In ri rf N ep d~ .1 C7 00
Q . a . . . . . . .
.
~,x o ci o 0 0 0 0 0 0 0 -
~w
U
_ -~ -~ __ - -_ -_ _- ----
O I
H ..,
H y
> ro ~ ' 0 -1 a d d .~ d c~
-1
H L ~
0
r~ c~ o a o o o o o 0 o a
'.x
~w
U
a c
__ __ __ __ __ ,_ -_ __ -
x a rv
v
w Oo m
S.1 ~ tl')tf1 N
'-1
U O O -1 a o N ~ .-io ~ ~r r
4 r~ O)
.
xI' a~x o 0 0 0 0 0 0 0 0 0
Z
G __ ~ -_ _- " -_ __ -- -- -
o
= w n
ro ~ -~ a o a a~ ~ .-,a v
~
g O
> -~ o, o a o 0 0 0 0 0 0 0
.
~
x
~'
g
c
~O CO N I ~'1
et N .-i d tD 1 ' O
~D 1 I N f~ x Ul N
N ~; H N 1 (;
r1 h ro N -3 rlI
ar m c~ cn m ;n w c
v a, ro -~ O ~ ~ ~ O
m ro o -~ c y a~ ro ~ y
C ~ ..1 ~ L U ~ T
m ~ ~
o v~ ~ ~ y c~ o
O ..a ~ .~ ~ ro ro ro
c ~ ~ ~ s~ s~ ~ ~, c~)
ro U C) y y ~U :JItn
T L) G T ro ~ ~ ;I1 ;,~n
1.~ S.~ 'JriJ U U ~ ~ ~
i
O O ~1 y m U J U U U
~i ro y b O O U J U
U s: ~ SJ C ~J U O O O
c0 C) -i O O O U J :)
:U .~ y :o .-~~ O O Q
o _~ .-~~ o a, >, .~
11 '!)y 'T3 ~ ~ w O.,Or
y .O ~ ~ f.~.Or y ~:.~y
~i ~~ o y r~ v a z~
C o) --~f.~u) y y y ~ .i.r'
ra s) x a) o. ~n cn ~n co ;n
~.
. 1340695
-17- _
The compounds of the inven tion ar a capable of
forming both pharmaceutically acceptable acid addition
and/or base salts. - Hase salts are formed with metals
or amines, such as alkali and alkaline earth metals or
organic amin~as. Examples of metals used as cations
are sodium, potassium, magnesium, calcium, and tha
1 ike. Examp:Les of suitable amines are N,N'-
dibenzylethy:ienediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methylglucamine,
and procaine.
Pharmaceutically acceptable acid addition salts
are formed with organic and inorganic acids.
Examples of suitable acids for salt formation
are hydrochl~~ric, sulfuric, phosphoric, acetic,
citric, oxalic, malonic, salicylic, malic, gluconic,
fumaric, succinic, ascorbic, malefic, methanesulfonic,
and the like. The salts are prepared by contacting
the free base form with a sufficient amount of the
desired acid to produce either a mono or di, etc salt
in the conventional manner. The free base forces may
be regeneratEad by treating the salt form with a base.
For example, dilute solutions of aqueous base
may be utilized. Dilute aqueous sodiu.~ hydroxide,
potassium carbonate, ammonia, and sodiun bicarbonate
solutions are suitable for this purpcse. The free
base firms differ from their respective salt forms
somewzat in certain physical properties such as
solubility in polar solvents, nut t'ze salts are
otherwise eq;iivalent to their respecti~: a free base
forms for purposes of the invention. :~' of excess
base where R' is hydrogen gives the corresponding
basic salt.
The compounds of ti:e invention can exist in un-
solvated as well as solvated forms, including hydrated
3 5 forms . In gE~naral , the solva ted fo r::us , i nclud irg
hyd rated forms and t:~a i ike ar a eau iva l ent to the
unsolvated forms for ourooses of the invention.
-1 g
The alk~~l grou~os contemplated by the invention
comprise, both straight and branched carbon chains of
from one to <~bout three carbon atoms except when
specifically stated to be greater than three carbon
atoms. Representative of such groups are :ethyl,
a thyl , propy7. , isopropyl , and the 1 ike.
The cycl,oalkyl groups contemplated by the inven-
tion comprise those having three to six carbons atoms
such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyc 1 ohe xyI .
. The term, haloalkyl, is intended to include ha7:o-
gen substituted straight and branched carbon chains of
from two to four carbon atoms. Those skilled in the
art will recognize that the halogen substituent may
not be present on the a-carbon atom of the chain.
Representative of :>uch groups are g-f7.uoroethyl,
S-chloroethyl, g, E3-dichloroethyl, g-
chloropropyl, g-chloro-2-propyl, y-iodobu:.yl, and
the like.
The terra halogen is intended to include fluorine,
chlorine, bromine, and iodine unless otherwise
specified.
Certain compounds of the invention may exist in
optically active farms. The pure D isomer, pure
isomer as well as mixtures thereof; including the
racemic rr~.ixtures, are contemplated by the invention.
Additional assymmet:ric carbon atoms may be present in
a substituent such as an alkyl group. All such
isome::s as well as mixtures thereof are intended to be
s0 included in the invention.
The compounca of the invention can be prepared
and administered in; a wide variety of oral and paren-
teral dosage forms. It will be obvious to those
skilled in the art that the following dosag a forms may
comprise as the active component, eit:~er a cotnpot:nci at=
foraula I or Ia or a corres~ndin~~ pharma~:euticallw
acceptat~le salt of ,~ compound of formula I or Ia.
~
. .
1340695
-19-
For preparing pharmaceutical compositions from
the compounds described by this invention, inert,
pharmaceutically acceptable carriers can be ei.the r
solid or liquid. Solid form preparations include
powders, tablets, dispersable granules, capsules,
cachets, and suppositories. A solid carrier can be
one or more substances which may also act as diluents,
flavoring agents, solubilizers, lubricants, suspending
agents, binders, on tablets disintegrating agents; it
can also be a.n encapsulating material. In powders,
the carrier is a finely divided solid which is in
admixture with the finely divided active compound.
In the tablet. the active compound is mixed with
carrier having the necessary binding properties in.
suitable proportions and compacted in the shape
and size desired. The powders and tablets preferably
contain froia 5 or 10 to about 70 percent of the active
ingredient. Suitable solid carriers are magnesium
carbonate, magnesium sterate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methyl
cellulose, sodium c:arboxymethyl cellulose, a low
melting wax, cocoa butter, and the like. The terra
"preparation" is intended to include tile formulation
of the active compaund with encapsulating material as
carrier providing a capsule in which the active com-
ponent (with or without other carriers) is surrounded
by carrier, Which i.s thus in association with it.
Similarly, cachets are included. Tablets, powders,
cachets, and capsules can be used as solid dosage
forms suitable for oral administration.
Liquid form preparations include solutions
suspensions and emulsions. As an example may be
mentioned water or water-propylene glycol solutions
for parenteral injection. Such solutions are prepared
so as to be acceptable to biological systems
(isotonicity, pH, etc). Liquid preparations can also
1340695
-20-
be formulated in solution in aqueous polyethylene
glycol solution. ~ueous solutions suitable for oray
use can be pry=pared by dissolving the active component --
in water and adding suitable colorants, flavors,
stabilizing, and thickening agents as desired.
aqueous suspension suitable for oral use can be rzade
by dispersing the finely divided active component
in water with viscous material, i.e., natural or
synthetic gums, resins, methyl cellulose, sodium
carboxymethyl cellu.iose, and other well-known
suspending agents.
Preferably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is
subdivided into unit doses containing appropriate
quantites of the active component. The unit dosage
fore can be a packaged preparation, the package con-
taining discrete quantities of preparation, for
example, packeted tablets, capsules, and powders in
vials or ampoules. The unit dosage form can also
be a capsule, cachet, or tablet itself or it can be
the appropriate numbar of any of these packaged fo ~. .
The quantity of active compound in a unit dose
of preparation may be varied or adjusted frow 1 ~g
to 100 mg according to the particular application
2 5 and the co tenc:y of the ac tive ing red Tent.
In therapeutic use as agents for treating bacter-
ial infections the ~~ompounds utilized in the phar-
maceutical mei_hod of this _zvention are administered
at the initia:L dosage of aaout 3 mg to about ~0 mg per
kilogram dail;~. A daily rose range of aoout 6 mg to
about 14 mg per kil~x7ra~~: is preferred. TLze dosages,
however, may be varied ciecending upon the requirements
of the patieni~, the se~ierity of the condition boring
treated, and the co;:,vound beinu e:nPioyeci.
Deteraination of th~~ proper dosac3e i.~,r a particular
s i tuation is tai thin tile skill of the art. ~nerally,
x
X340695
-21-
treatment is initiated with smaller dosages which are
less than the optimum dose of the compound.
Thereafter, the dosage is increased by small
increments until the opti~~u:n effect under the
circumstances is reached. For convenience, the total
daily dosage may be divided and administered in
portions during they day if desired.
The following nonlimiting examples illustrate
the inventors' preferred methods for preparing the
compounds of the invention.
PREPARATION OF STARTING MATERIALS
EXAMPLE A
1-Ethenyl-~, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-
qu inol inecarboxyl is ac id
6, 7, 8-Trifluoro-1, 4-dihydro-4-oxo-3-quinoLine
carboxyl is acid ethyl ester is treated with dibromo
ethane to afford the I-ethenyl-6, 7, 8-trifluoro-I, 4-
d ihyd ro-4-oxo-3-qu inol inecarboxyl is ac id ester, mp
134-135°C. S~.~bsequent hydrolysis with hydrochloric
acid gave 1-ethenyl-6, 7, 8-trifluoro-1, 4-dihydro-4
oxo-3-quinolizecarboxylic acid, mp I86-187°C.
EXAMPLE B
5, 7, 8-Trifluoro-1-( 2-fluoroethvl )-l, 4-dih~w-: ~o-4-oxo-
2 5 3-:3u inol neca rboxyl is ac id
in identical fa5tiion, 6, 7, 8-~ritluoro-~, 4-
dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester
was converted w~ th fluorobrorr~oethane to 6, T, 8-tri-
f luo ro-1-( 2-f:luo roetriyl ) -1, 4-d ihyd ro-4-oxo-3 ~u inol ine
3 0 carboxyl is «c id , m. o ~ 20?-211 °C .
,,
1340695
-22-
EXAMPLE C
1-Cyclopropyl-6, 7, ~3-trifluoro-1, 4-dihydro-4-oxo
3-qu inol inecarboxv7. is ac id
2,3,4,5-tetrafluorobenzoylacetic acid, ethyl ester
To 25. 2 g (0. 117 mole) of sodium 2, 3,4, 5-tetra-
fluorobenzoat:e, prepared as a dry powder from 2, 3, 4,
5-tetrafluorobenzo is ac id [J . Org . Chem. 29, 2381
(1961)] and a~queou~~ sodium hydroxide with concentra-
tion to dryness, was added 400 ml of dry ether and
the suspension was cooled to 0°C. Slowly 25 ml
(- 2.5 equivalents) of oxalyl chloride in 50 ml
of ether was added and the mixture brought to room
temperature ~;rhere it was maintained for 2.0 hours.
It was filtered and concentrated to remove low
bo il ing impur i ties .. The res idue was d issolved in
100 ml of ether and placed in an addition funnel.
Meanwhile, 2.9 c~ (0.119 mole) of magnesium
turnings were treated with 100 ml of absolute
ethanol and 0~.3 ml of carbon tetrachloride. To this
mixture was added 13.6 ml (0.12 mole) of diethyl
malonate in 75 ml of ether a.t a rate to keep the tem-
perature just. below reflux. Tdhen addi~ion was com-
plete, the reaction was refluxed for two hours. At
-20°C, the et.here3l. acid chloride was slowly added.
When addition. was c:onplete, the reaction was brought
to 0°C over 13 hours. The mixture was poured into
dilate hydrochloric: acid and was extracted into
d ichlorome thane which was dried (I~!g504 ) and concen-
trated. The residue was then treated with 340 mg
p0 of p-to.luenesulfons.c acid in 600 ral of water at
100°C roL two hourL; with rapi;i stirring. The oil was
extracted into dicr~loromethane, dried (~!gS04) and
concentrated. The residue was purifie3 by colu~~n
. ~34oss5
.
-23-
chromatography (Silica gel, using toluene:hexane:
a then 4: 5 :1 ) , to g ive 18. 5 g of a redd ish o il . Th is
material was triturated with pentane to give 10.2 g
of 2,3,4,5-tetrafluorobenzoylacetic acid, ethyl. ester,
mp 49-51°C.
2-(2,3,4,5-tetrafluorobenzoyl)-Z-cyclopropylamino-
acryl is ac id , e_ thyl es ter
To 10.16 g (38. 5 mmole) of the 2-(2, 3, 4, 5-tetra-
fluorobenzoylacetic acid, ethyl ester was added
8.43 g (57.0 :mmole) of triethylorthoformate and 9.34 g
(91.5 mmole) ~of acetic anhydride. The mixture was
heated to 150'°C for two hours and was then placed
under high vacuum at 75-85°C for one hour. The
residue disso:Lved, without purification, in 100 ml of
isopropyl alcohol and treated with 2.4 ml of
cyclopropylam.ine. The reaction stood overnight. It
was concentrated and pur i f ied by column chroma tog raphy
( Sil ica gel 70-200, us ing hexane:chloroform: isopropyl
al cohol , 80 :1:5: 5 ) . Th a produc t of f the column was
recrystallize<9 froia pentane to give 6.16 g of 2-
(2, 3, 4, 5-tetrafluorobenzoyl )-Z-cyclopropylamino-
acrylic acid, ethyl ester, mp 63-64°C.
1-Cyclopropyl--6, 7, 8-tri~luoro-1, 4-dihydro-4-oxo-3-
qu inol inecarb«xyl is ac id .
Z5 To 2. 0 g (6. J mole) of the 2-(Z, 3, 4, 5-tetra
fluorobenzoyl;!-~-~:y~:! opropylaminoacryl is acid,
athyl estor in 5G .nl of dry dioxane was added 0.29 c3
of sodium :rd~:ide (50~ dispersion) that was prewashed
with penta::e. ~r.e sodium hydride was delivered in
10 ml cF dry t=etrahydrcfuran at 0°C. When evolution
of hydrogen began to slog, the mixture was re fluxed
for two hours., It was concentrated, and the residue
taken up in d:LCf'31'JL't;,.T~?thane, which was water
extracted, dried (~i<3504) and concentrated. ~'hs
-2 4-
I340fi95
residue was purified by column chromatography (Silica
gel 70-200 mesh, using chloroform: hexane:isopropanol,
4 : 5: 1 ) to g ive 0. 95. g of the 1-cyclopropyl-6 , 7, 8-
trifluoro-1, 4-dihydro-4-o:co-3-cuinolinecarboxy.Iic acid,
ethyl ester, mp 168-169°C. This material was dissolved -
in acetic acid at 1.00°C and was treated with IO ml
of 0.5 N hydrochloric acid for 2.5 hours. The mixture
was cooled and water added. The solids were then
collected to give 0. 7 g of 1-cyclopropyl-1, 4-dihydro-
4-oxo-6, 7, 8-tr ifluoro-3-qu inol inecarboxyl is ac id,
mp 226-228°C. _
EXAMPLE D
7-Chloro-1-cyclo~ropyl-6-fluoro-1,4-dihydrc,-4-oxo-
1, 8-naphthyr id ine- ~-carboxyl is ac id
4-[6-(Cyclopropylamino)-3-vitro-2-pyridinyl]-
1-oiperazinecarboxylic acid, ethyl ester
A solution of 126.0 g (0.4 mole) of 4-(6-chloro-
3-vitro-2-pyridinyl.)-1-piperazinecarboxylic acid,
ethyl ester (prepared as described in Es rope an Patent
Publ ication ~to. 9425 ) , 76.1 g ( 0. 5 mole) of I, 8-
diazabicyclo[5.4.0]lundec-7-eve (D8U), 28.6 g (0.5 mole)
of cyclopropylamine~ and 500 ml of absolute ethanol was
stirred at room temperature for 48 hours. The
solution was then heated ac reflux for four hours and
concentrated in va<:uo. The residue was partitioned
between chloroform and water. The chloroform layer
was dried over :nacJnesium sulfate and corce~trated in
vacuo) The residue was triturated witi~ ether to give
64.0 g of thE~ title compound, mp 100-103°C.
1340695
-2 5-
4 =[6-(Acetylc-yclopropyian;ino)-3-nitLo-2-pvridinv? J -
1-pi~razinecarboYj~lic acid, ethyl ester
A solution of 64.0 g (0.19 mole) of 4-[5-(cyclo-
propyl,:mino)-3~-Ilitra-2-pyridinyl]-1-piperazine-
carboxyl is ac: id, et:nyl ester, 115 ml of acetic
anhydride and, 115 ml of acetic acid was heated on a
ste~an bath for 36 hours. The solvents were removed in
vacuo, the residue was triturated with a mixture of
a thanol and toluene wh ich was also evapora t:ed in vacuo
to give 68.3 g of t:hs title compound, mp 90-93°C.
4- [ 6-( ac a tylcyc lopropyl a:~~ino) -'3-zmino-2-pyr id inyl ] -1-
piperazinecarbox~lic acid, ethyl ester
A mixtures of 1,7.0 g (45 mmoie) of 4-[6-(acetyl
cyclopropyl air,~ino) - 3-nitro-2-s:yr i~3 i nyl-1-piperazine
I5 carboxylic ac: id, et:hyl ester, 1.5 g of :taney nickel
and 180 ml of: absolute ethanol was shakes: in a
atmosphere of. hydrogen at about 5U psi and room
temperature f:or approximately 24 hours. The catalyst
was removed by f il t:er ing tnrcu:; ~: Ce 1 i t~ anc~ the
solvent removed in vac~uo to ~~ive 15.2 g of the title
compound, mp 149-150°C.
2-[4-( H thoxyc~arbon~~:~ ~ -1-:.~.pPrav:~nlrl ] -6-
{acet:rlcwclo ~ropyl~:a:ino~- -p ~ric:ine;3iaycniu:n
tetratluoroborate
A solution of 20.8 ~; ;~~0 :n,-r~ole) of 4-(6-acet~t.-
cyclopropylarr~ino)-.,-~~ :-::~-'_-=lciai::i~l]-1-piperazine-
c arboxyl is ac: ? d , a;::~yl. p - ::.-: , -~~~ ml of a thanol and.
2'' ml of 48~ tetraf=uox~;.r~.::;~:~c acid was cooled to 0°~~
and treated clropwise wt:i a soi;.iion of 4.56 g {60
rmoie) of sodium nitrite in 8 ml of water under
nitrogen at~nc~spher:: keef.~in, the ta:aparature 0-.,'v.
~f'ar tile ad;:;ition waa cmnplet2, t':e reaction was
s ~.:;rrec~ at 0-~~°C fc;r o::s 'your and tr°ate:: wi t!i i5u
~::i
.:f anizydrou:~ ether keeping t'~e te~nperatu.rp beJ.o;a '_~.)°C.
* trade mark
_ 1340695
-26-
The solid was removed by filtration, the precipitate
was washed with ethanol/ether (1:1) , ether and dried
in vacuo to give 24.5 g of the title compound, mp
100-105°C (den. ) .
4-[6-(Acetylcyclopropyl amino)-3-fluoro-2-pyridinvlj-
1-piperazinecarboxy.lic acid, ethyl ester
To 800 ml of refluxing toluene was added in
portions, as a solid, 46.2 g (0.1 mole) of
2-[4-( a thoxycarbony:L ) -1-piperazinyl j -6-{acetyl-
- 10 cyclopropylam:ino)-3-pyridinediazonium tetrafluoro-
borate. After the .addition was complete, the reaction
was refluxed i:or ten minutes and the toluene was
decanted from the insoluble precipitate. The toluene
was evaporated in vacuo and t:~e residue was partition-
ed between ch~.orofo:rm and water. The chloroform layer
was washed with 5~ aqueous sodium bicarbonate, water,
dried over mac~nesiurn sulfate and evaporated in vacuo
to give 13.7 ~~ of the title compound, as a viscous
oil. An additional 10.2 g could be obtained by
partitioning t:he original toluene insoluble material
in chloroform and water. The organic Iayer was washed
with 5~ aqueou,s sodium bicarbonate, dried over
magnesium sulfate, Evaporated in vacuo and the residue
was chromatogz-aphed on silica cel eluting with
chloroform/eti~yl acetate (6:4). This fraction was
also a viscous oil which did not crystallize upon
standing. Both fractions caere of sufficient purity to
be used as is in thE: ens~.:ing steps .
4-[6-(Cycloprc~u~ ylami~no)-3-fluoro-2-pyridinylj-1-
pin~erazinecartoxv? is acid, ethvi ester
A solution of 27..9 g (63 mmola_) oL 4-[ti-{acetyl-
cyclopropyl amino}-3--fluoro-2-pyri::;nyl j-1-piperazine-
carooxylic acid, ethyl ester, i70 ~.n~_ of 153
hyd rociiloric ac is arW 235 ml of ,net:~anoi ~,~as refiuxed
~3~~095
-2 7-
for one' hour and allowed to stir at roo;n temperature
for 18 hours. The methanol was removed in vacuo and
the aqueous a~;. id was made bas is wi th 1. 0 N sod ium
hydroxide to ,pH 10.5. The mixture was extracted with
S chloroform, t',he chloroform layer washed with water,
dried over ma~3nesiuam sulfate, and evaporated in vacuo
to give 17.6 ~3 of the title compound, mp 68-70°C.
EXAMPLE E
1--Cyclopropyl~-6-fluoro-1, 4-dihydro-4--oxo-7-(L-
piperazinyi)-:1,8-naphthyridine-3-carboxylic acid
Route A
1-[Cvclopropy:L[o-[4-(ethoxycarbonyl)-1-piperazinyl]-
5-fluoro-2-pyr id inyl ] amino] me thyl ene] propaned io is
acid, diethyl ester
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclo-
propyl amino) -:3-fluoro-2-pyr id inyl ] -1-piperazine-
carboxyl is acid, ethyl ester, 2. 7 g (12. 3 mmole) of
d ie thyl ( a tho;cyme th:yl ene ) mal ono to and 50 ml of xyl ene
was refluxed :Eor 24 :ours. The solvent was removed in
vacuo and the residue was chromatographed over silica
gel eluting with ch.lorororm/ethyl acetate (80/20) to
give 2.3 g of the title compound as a v~'_scous oi:L
which was usec3 without furtrier purification.
Ethyl 1-Cvclopronvl~-5-=luorc-- i, -~ -d i,lyd ro-4-oxo-
7-[4-(ethoxyc<~rbony:l )-1-piaer=zvic~~ -I, 8-
2 5 naphthyr id ine--3-car;:,oxvl ate
A solution of 2. 3 g (4. 8 -urole) of [ [cyclo-
prcoyl [ 6-[4-(ethoxycarbonyl )-1-pii.erazinv? ] -5-
fluoro-2-p~;ri~3iny1],~-nino]~:ethyler.e] ~ropanedioic
acid, dietayl ester, in i5 :n! of ,acetic anhydride was
treated drocw~.se wit'_~. 5 ~~1 or 93v s~~iit!ric aci;,;
keeping the tE.mperat~zre 35-60°~, w;.er: the 3daition
l~4oss5
-2 8-
was complete, the i:eaction was stirred for one hour
and poured onto 50 g of ice. The aqueous suspension
was extracted with chloroform, the chloroform layer
washed with water, dried over magnesium sulfate,
filtered, and evaporated in vacuo. The residue was
triturated with several portions of ethanol/toluene
which were also removed in vacuo to give 0.4 g of the
title compound, mp 184-186°C. An additional 0.5 g of
produc t could be obtained by concentrating the
original aqueous fraction, mp 184-186°C.
1-Cycloprop I-6-fluoro-1,4-dihydro-4-oxo-7-
(1-piperazinyl)-1,8-naphth ridine-3-carboxylic ac id
A suspension of 0.7 g (1.6 mmole) of ethyl
1-cyclopropyl-6-fluoro-1, 4-dihydro-4roxo-7-[4-
a thoxycarbonyl ) -1-piperazinyl ] -1, 8-naphthyr id ine-
3-carboxyl ate , 6 ml of 10$ aqueous sodium hydroxide
and 2 ml of ethanol was refluxed for three hours. The
reaction was filtered through a fiber glass pad to
clarify and acidified to pH I.5 with 6.0 M hydro-
chloric acid .and lyophilized. The residue was
dissolved in .10 ml of ammonium hydroxide and the
solution concentrated in vacuo. The precipitate which
formed was removed by filtration, washed with aqueous
ethanol, ether and dried in vacuo to give 0.04 g, mp
274-276°C.
Route H
4-r~~-[Cyclopronyl ( 2, 2-dimethyi-4. 6-d _oY:~-1, 3-dioxan-
5-yi id ine) amino] -3-fluoro-2-pyr ici irzvl; -:~.-~ieerazine-
c arboxyl is ac id , a t~hyl es to r
A solution of 17. 6 g (57 moral ?; cf 4-[cs-(cycl~o-
propylamino)-3-fluorc-2-pyridinyil -~,-r.i~erazine-
carboxylic ac:Ld, ethyl ester, '_3.0 7 ;03 nmole) of
5-( me thoxyme t:~yl ene;) -2, 2-d its tt:_r L-1. 3-~ ion: aria-4 , 6-a ione
and 250 ~nl of methanol was .stirre~3 at :~c~,~ temperature
._.. ~ ,
.~
1340695
-2 9-
for four hours. The solid was removed by filtration,
washed with methanol, ether and dried in vacuo to give
17.6 g of the title compound, mp 177-178°C.
1-Cyclopropyl,-6-fluoro-1, 4-dihydro-4-oxo-7_-[4-
(ethoxycarbon 1~-1--piperazinyl) -1, 8-naphthyridine-
3-carboxyl is ac id
A solution of 17.0 g (37.0 mmole) of
4-[6-(cyclopropyl ( 2, 2-dimethyl-4, 6-dioxo-1, 3
d ioxan-5 yl id.ene) amino) -3-fluoro-2-pyridinyl) -1-
piperazinecarboxyl is acid, ethyl ester ir. 125 ml of
acetic anhydride was treated dropwise with 35 mI of
98$ sulfuric acid keeping the temperature 5U-60°C.
When the addition was complete, the reaction was
stirred for t,wo hours and poured onto 600 g of ice.
The mixture was stirred was stirred for one hour and
the resulting precipitate was removed by filtration,
washed with water and dried in vacuo to give I0.2 g ar
the title compound, mp 277-279°C.
1-Cyclopro~xl-6-fluoro-1, 4-dihydro-4-oxo-7-
(1-piperaziwl)-I,8-naphthvr idine-3-carboxylic acid
A solution of 1Ø2 g (25 mmole) of 1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-
piperazinyl ) -l, 8-naphthyr id ine-3-carboxyl is ac id,
100 ml of 10~ aqueous sodium hydroxide and 40 ml of
ethanol was refluxed for three :zolirs. The solution
was concentrated to 125 ml and at: za if ied to pH 7. 3
with glacial acetic acic:, r~-~e r:~sul ring precipitate
was removed by filtrati~~;~, ~uashed ~,~i th 50~ aqueous
ethanol, ether and dried in va~uo to give 7.2 g of the
title compound, mp 274-2~5°.
1-Cyclo~ropyl ~-6-fluoro-1, 4-dihydro-7-hydrox~r-4-oxo-
1, 8-naphthyr id ine-3-carboxyl is ac i
To a solution of 2 ml ox 7Ub nitric acid in
10 ml of 98~s aulf~aric acid was added in portions
-- - .~ ~ . , 1340695
-30-
1.0 g (3.0 mm~ole) of 1-cyclopropyl-6-fluoro-1,4-
dihydro-4roxo-7-(1--piperazinyl )-1,8-naphthyr idine-3-
carboxylic acid, keeping the temperature between
25-30°C. The resulting solution was stirred at
room temperature far 18 hours and poured onto .~0 g
of ice. The mixture was stirred at room temperature
for 24 hours, concentrated in vacuo, the pH adjusted
to 12 with aqueous sodium hydroxide, and filtered
through a fiber glass pad. The filtrate was
acidified to pH 3.5 with 6.0 M hydrochloric acid,
the resulting precipitate removed by filtration,
washed with water then ether and dried in vacuo to
give 0.23 g of the title compound, mp 325-327°C.
7-Chlaro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
1, 8-naphthyr id ine-3-carboxyl is ac id
A suspension of 0.19 g (0.72 mmole) of
1-cyclopropyl-6-fluoro-1, 4-dihydro-7-hydraxy-4-oxo-
1, 8-naphthyr i,d ine-3-carboxyl is ac id in 2 mI of
phosphorus ox;ychloride was heated at reflux for
1/2 hour. The resulting solution was cooled to
room temperature and the solvent was removed in
vacuo: The residue was triturated with ice-water
and the resulting solid was removed by filtration,
washed with wa ter, then ether and dried in vacuo
to give 0.11 ~~ of the title compound, mp 209-212°C.
EX.~MPLE r~
3-Endo( acet~ 1.~-nino)-8-azabicyclo[3. 2. J.joctane hvdro-
~.y,1 nr;~o
3-Endo(-acetyl,~nino)-3-(phenyl methyl)-8-azabicyclo-
[3.2.1Joctane, hydrochloride
A solution of 5.2 g (28 r~uaoLe) of 3-(endo-a~~ino)
8-(phenyl methyl)-8-aabicyclo[3.2.1]octane [J. ~.
Bayiey and T. V. htilay, J. Heterocyclic Chem., 19, -X85
4340695
-31-
(1982)], 2.84 ml (40 mmole) of acetyl chloride and 50 ml
of acetonitrile was stirred at room temperature for two
hours. The reaction mixture was filtered to give
3.70 g of the title compound, mp 203-204°C.
S 3-Endo(acetylamino)-8-azabicyclo [3.2.1]octane, hydro-
chloride
A mixture of 3. 58 g ( 11. 2 mmole) of 3-endo
(acetylamino)-8-(phenylmethyl)-8-azabicyclo[3.2.1]
octane hydrochloride, 0.4 g of 20$ palladium on carbon
and 100 ml of methanol was hydrogenated until the
requisite uptake was observed. The reaction mixture
was filtered and the filtrate was evaporated to dry -
ness to give 2.79 g of the title compound which was
used without further purification.
EXAMPLE G
3-Exo(acetyl~~nino)-8-(phenylmeth~-8-azabicyclo
[3.2.1]octane, hydrochloride
A solution of 4.6 g (20 mmole) of 3-(exo-aminoY)-8-
phenylmethyl;l-8-azabicyclo[3.2.1]octane [J. R. Bagley
and T. N. Ri:ley, J. Heterocyclic Chem., _19, 485 (1982)j,
10 ml of acetic anhyd ride and 100 m1 of acetic ac id
was heated under reflux for two hours. The reaction
mixture was evaporation and the residue was dissolved .
in acetonitrile and 6N HCl in 2-propanol. The solution
was filtered and the filtrate ;aas evaporated. The
residue was recrystallized from acetonitrile-ethyl
acetate to gave 2.:30 g of the title compound, mp 217-
219°C.
3-Exo(acetyl~unino)--8-azabicyclo[3.2.1]octane, hydro-
chloride
A mixture of .2. 23 g (7. 56 nunole) of 3-exo( acetyl-
amino)-8-(phenyl methyl ) -8-azabicyclo[3. 2. 1] octane,
~34oss~
-3 2-
hydrochloride, 0.2 g of 20$ palladium on carbon and
100 ml of methanol was hydrogenated until the
requisite amount of hydrogen was taken up. The
reaction mixture was filtered and the filtrate was
evaporated to yield 1.5 g of the title compound which
was used without further purification.
EXAMPLE H
3-(Exo-amino)-8-azabicyclo[3.2.1]octane, dihydro-
chloride
A mixtm:e of 4.6 g (20 mmole) of 8-(phenylmethyl)
8-azabicyclop.3.2.1,]octan-3-one, oxime [J. R. Bagley
and T. N. Ri7.ey, J.. Fieterocyclic Chem., _19, 485 (1982) ] ,
0.5 g of 10~ rhodi~un on carbon, and 100 ml of acetic
acid was hydi:ogenated until the requisite amount of
hydrogen was taken up. The reaction mixture was
filtered and two equivalents of HC1 was added. The
solid was filtered to yield 2.80 g of the title
compound, mp >300°C.
EXAMPLE I.
3-(Endo-amino)-8-azabicyclo[3.2.1]octane, dihydro-
chloride
A solution of 7.33 g (25 mmol) of 3-(endo
amino) -8-( phe~nylmei=hyl ) -8-azab icyclo [ 3. 2. 1] octane
dihydrochlori.de [P.. Dostert et al, Eur. J. fled. Chem.-
Chim. Ther., 19, 105 (1984)], 1.0 g of 20$ palladium
on carbon and 100 ml of methanol was hydrogenated
until the required amount of hydrogen was taken up.
The reaction mixtux-e was filtered and the filtrate
was evaporated to 4.5 g of the title compound which
was used wit:~.out purification.
1340695
-33-
EXAMPLE J
1-Cyclopropy:L-7-(ethylthio)-6-fluoro-I, 4-dihydro-
4-oxo-1,8-naphthyr idine-3-carboxylic acid
A solution of 3.4U g (12 mmol) 1-cyclopropyl-7-
chloro-6-fluc~ro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-
3-carboxylic acid in 60 ml N,N-dimethylformamide
heated to 60'°C was treated with a solution of 3.36 g
(60 mmol) potassium hydroxide and 6 ml (81 mmoi)
ethanethiol in 30 ml absolute ethanol. After
IO stirring 15 minutes at 60°C the mixture was poured
into 240 ml ice cold 0.5N hydrochloric acid, and the
precipitate was filtered, washed with water and
crystallized from acetic acid - water to give 3.10 g,
mp 242-244°C of the title compound.
1-Cyclopropy7L-7-(ethanesulfonyl)-6-fluoro-1,4-
d ihyd ro-4-oxcrl, 8-naphthyr id ine-3-carboxyl is ac id
A solution of 0. 20 g ( 0. 65 mmol ) 1-cyclopropyl-
7-(ethylthio)-6-fluoro-4-oxo-1, 4-dihydro-1, 8-
naphthyr id inc:-3-carboxyl is ac id in 2 ml trifluoro-
acetic acid was stirred in an ice bath and treated
dropwise with 0.4 m1 30$ hydrogen peroxide. The
bath was removed, :stirring continued 4.75 hours,
and the mixture poured into ice water. Filtration
afforded 0.20 g of the title compound, mp 240-
242°C.
EXA:~PLE K
1-Ethyl-7-(et:hyl tth:io)--6-fluoro-1, 4-dihydro-4-oxo-1, 8-
naphthyr id inE~-3-car box~l is ac id
A suspension of 0.54 g (2 mmol) 1-ethyl-7-
chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-
3 -carboxyl is ac id :i.n 10 rnl N, N-d iris thyl forma~uide
was stirred at 60°<~ and treated all at once with
134069
-3 4-
a solution o:E 0.56 g potassium hydroxide (10 mmol)
and 1 ml (O. ;B5 mmol) ethanethiol in 5 ml absolute
ethanol. After 15 minutes the mixture was poured
into 40 mmol 0.4 N hydrochloric acid containing ice.
The precipitate was filtered, washed with ethanol
and ether to afford 0.46 g of the title compound.
A sample for analysis was crystallized from acetic
acid, mp 219--221°C.
1-Ethyl-7(etlzanesulfonyl)-6-fluoro-1, 4-dihydro-4-
oxo-1, 8-naphi_hyr id ine-3-carboxyl is ac id
A solution of 3.29 g (11 mmol) 1-ethyl-7-
(ethylthio)-6-fluoro-1, 4-dihydro-4-oxo-1, 8-
naphthyr id ine-3-carboxyl is ac id in 3 0 ml
trifluoroacettic acid stirred in an ice bath was
heated dropw~ se wi th 6. 6 ml ( 73 mmol ) 30$ hyd rogen
peroxide. The batlh was removed and stirring was
continued at room temperature for 4.75 hours. The
mixture was prepared into 300 ml ice water and the
precipitate 1°iltered to afford 3.46 g of the title
compound, mp 249-252°C.
134oss5
-3 5-
EXAMPLE 1
7-( 2, 5-Dia_za,b is cl_o(2. 2 2] oct-2-Y1 ) -1-eth~~l=Toro=
d h dro-~4-oxo- 3 ~u inol inecarboxyl is ac id
1,
A solution of 0.52 g (2.0 mmole) of
th 1-6,7-difluoro-1,4-dihydro-4-oxo-3-<iuinoline-
1-a Y
carboxylic acid, 0. 37 g (2. 0 mmole) of 2, 5-diazabicyclo
(2.2.2) octane dihydrochloride [P. A. Sturm et al.,
J: Med. Chem., li!, 481 (1974)]. 0.90 ml (6.0 mmole) of
1,g-diazabi.cyc1o1.5.4.0]undec-7-ene and 25 ml of
acetonitril.e was heated under reflux for 21 hours.
The reaction mixture was filtered and the filtrate was
evaporated to dryness. The residue was recrystallized
from ethan~~l to give 0.30 g of the title compound,
mp 270-272°.
EXAMPLE 2
7-(2,5-D_i<~zabic c:Io[2 2.2]oct-~ 1~ 6-=""
difi "~L~-4-didih~rdro-4-oxo-3 uinolinecarbox lic acid
A solution .of 0. 81 g (3. 0 mmole) of 1-ethyl-6 r 7, g-
trifluoro-1,4-dihydro-4-oxo-3"guinolinecarboxylic
0 acid, 0. T4 g (4.0 mmole) of 2, 5-diazabicyclo [2. 2. 21
2
octane di.hydroc:hloride [P. A. Sturn et al., J. ~d.
Chem. , I'l, 481 (1974) 1 , 1. 65 ml (11 mmole) of
l,8-diazabicyclo[5.4.0]undec-7-ene, and 40 ml of
aceton~trile was stirred at room temperature for
25 hours and heated under reflux for t~.vo hours.
reaction mixture was filtered. and the solid was washed
with me t.hanol to g ive 0. 68 g of the title compound
mp X55-~!57° .
13406g~
-3 6- _
EYAMPLE 3
7-( 2, 5-Diazabicycla[2. 2. 2] oct-2-yl )-1-cycloproDyl-6, 8
difluoro-1,4--dihydro-4-oxo-3-quinolinecarboxylic acid
A mixtu~:e of 0.28 g (1 mmole) of 1-cyclopropyl-
6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinoline-
carboxyl is ac: id, 0. 2 g (1. I mmole) 2, 5-diazabicyclo-
[2.2.2]octanE: dihydrochloride [P. A. Sturm et ai.,
J. Med. Chem", 17, 481 (1974)], 0.45 ml (3.0 mmole)
of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10 ml of _
acetonitrile was heated at reflux for four hours.
Af ter cool inch to roam temperature, the reaction
mixture was i:iltered and the solid washed with ethanol
and dried to gi-ee 0.27 3 of the title compourxd,
mp 275-280°C..
EXAMPLE 4
7-( 2, 5-Diazabicycla[ 2. 2. 2] oct-2-yl ) -1-ethyl-6-fluoro-
I, 4-dihyd ro-46-oxo-1, 8-naphthyr id ine-3--carboxyl is ac id
A solution of 0. 54 g ( 2. 0 mmole) of 7-chloro-1-
ethyl-6-fluoro-1, 4--dihydro-4-oxo-1, 8-naphthyridine-
3-carboxyl is acid, 0. 46 g ( 2. 5 mmole) of 2, 5-diazabi-
cyclo[2.2.2]octane dihydrochloride [P. A. Sturm et
al., J. Med. Chem., 17, 481 (1974)], L 05 ml (7.0
mmole) of of 1,8-diazabicyclo (5.4.0) undec-7-ene, and
ml of acet:onitrile was stirred at roam temperature
25 for 23 hours. The reaction mixture was filtered and
the solid was washed with acetonitrile to give 0.63 g
of the title compound, mp 250-253°.
1340695
7- _
EXA:IPLE 5
10-( 2, 5-Diaz;3b icyclo [ 2. 2. 2] oct-2-yl ) -9-fluoro-_2,_3-
d ihyd ro-3-me t~l _7,-oxo-7H-pyrido [ 1, 2, 3-de] -1, 4-
benzoxazine-~6-carbox ly is acid
A solution of 0.56 g (2.0 mmol) of 9,10-
difluoro-2, 3~-dihydro-3-methyl-7-oxo-7H-pyrido[1, 2, 3-
de]-1,4-benzoxazine-6-carboxylic acid, 0.41 g
(2.2 mmol) o:E 2,5-diazabicyclo[2.2.2Joctane
dihydrochlor:ide, 0.90 ml (6.0 mmol) of 1,8-
diazabicyclo[5.4.0]undec-7-ene, and 25 ml of ace-
tonitrile was heated under reflux for 18 hours.
The solution was e~~aporated to dryness and the
residue was i~riturated with methanol and filtered
to give 0.20 g of 'the title compound, 260-265°C.
EXA~~IPLE 6
In the Name manner as Examples 1-5, the following
compounds arE~ prepared from 2,5-diazabicyclo[Z.2.2j-
octane dihydrochloride and the appropriate quinoline
or naphthyridine intermediate:
7-( 2, 5-c~iazab:icyclo[ 2. 2. 2J oct-2-yl ) -1-
cyclopropyl-E>-fluoro-1,4-dihydrv-4-oxo-1,8-
naphthyridine:-3-carvoxylic acid (a); mp 265-270°C,
7-( 2, 5-cfiazab:icyclo [ 2. 2. 2] oct-2-yl ) -1-
ethenyl-6, 8-~iifluoro-1, 4-dihydro-4-oxo-3-quinoline-
2 5 carboxyl is ac: id ( b ) , and
7-(2,5-diazab:icyclo[2. 2.2]oct-2-yl)-(2-
fluoro-ethyl)-Ei, 8-difluoro-1, 4-dihydro-4-oxo-3-
qu inol inecart~oxyl ic: ac id ( c ) .
__.
1340695
-38-
EXA~PL~ 7
7-[2,5-Diazabicyclo(2.2.1)hept-2-yl]-1-ethyl-6,8-
difluoro-1,~4-dihydro-4-oxo-3-quinolinecarboxyTi.c
acid (a )
A solution of 0.54 g (2.0 mmol) of 1-ethyl-
6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-
cardoxylic acid, 0.57 g (2.2 mmol) of 2,5-diaza-
bicyclo(2.2.1)heptane dihydrobromide [P. S.
Portoghese and A. A. Mikhail, J. Urg. Chem., _31, 1059
(1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)
undec-7ene, and 20 ml of acetonitrile was heated under
reflux for one hour and stirred at room temperature
for two hours. The xeaction mixture was filtered and
the solid was washed with ethanol to give 0.60 g of
the title compound, mp 275°C.
In a similar manner the following compounds
were prepared:
7-[2,5-diazabicyclo(2.2.1)hept-2-yl]-1-ethyl-
6-fluoro-1,4-dihydro-4roxo-1,8-naphthyridine-3-
carboxylic acid (b), mp 233-6°C, .
1-cyclopropyl-7-[2,5-diazabicyclo(2.2.1)-
hept-2-yl]-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid, monohydrochloride
(c), mp 257-9°C,
1-cyclopropyl-7-[2,5-diazabicyclo(2.2.1)hegt-2-
yl.I-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoZinecarbaxy-
lic acid (d), mp 295°C, and
10-[2, 5-diazabicyclo( 2.2.1)hept-2-yl]-9-fluoro-
2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-
benzoxazine-6-carboxylic acid (e), mp 255-270°C.
' - ~ ~ . , 1340b9~
-39-
EXAMPLE $
1-Ethyl-6,8-~aifluoro-7-(5-methyl-2,5-diazabicyclo-
[2.2.2]oct-2-yl)-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid, hydrochloride
A solution of 1.15 g (3.0 mmole) of
7-( 2, 5-diazabicyclo [2. 2. 2] oct-2-yl ) -1-ethyl-6, 8-
difluoro-1, 4~-dihydro-4-oxo-3-quinolinecarboxylic acid,
ml of 37% formaldehyde solution, and 10 ml of 88%
formic acid was heated under reflux for four hours.
10 The reaction mixture was evaporated to dryness, l ml
of 6N hydrogen chloride in 2-propanol and 25 ml of.
alcohol was added and the mixture was heated. The
solid was filtered off and washed with athanol to give
0.98 g of the title compound, mp > 300°.
EXAMPLE 9
1-CyclopropyA-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-
diazabicyclo![2.2.2]oct-2-yl)-1,8-naphthYr idine-.~~
carboxylic ac: id monohydrochloride
A solution of 0.77 g (2.0 mmol) of 1-cyclopropyl-
6-fluoro-1,4--dihydro-7-(2,5-diazabicyclo(z.2.2]oct-
2 yl)-1,8-naphthyridine-3-carboxylic acid, 10 ml of
88% formic ac: id, and 10 ml of 37% formaldehyde
solution was heated under reflux for four hours.
After shirring the solution at room temperature over-
2 5 night, it was evaporated to dryness, and the residue
was treated with 6N HC1 in 2-propanol and etranol.
The solid wa:~ collected to give 0.45 g of the title
compound, mp > 310°C.
1344fi95
- -40-
EXAMPLE 10
1-Ethyl-6-fluoro-7-(5-methyl-2,5-diazabicrLclo-
(2.2.2)oct-2~-yl)-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid hydrochloride (a)
A solution of 1.16 g (3.18 mmole) of 7-(2,5-diaza-
bicyclo[2.2.2]oct-2-yl)-1-ethyl-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
ml of 37$ formaldehyde solution: and 10 ml of 88~
formic acid s,ras heated under reflux for four hours.
10 The reaction mixture was evaporated to dryness and
1 ml of 6N h;tdrogen chloride in 2-propanol and 25 ml
of ethanol w<~s added to the residue. After heating
this mixture the solid was filtered off. The solid
was dissolvec9 with 1N sodium hydroxide and
precipitated with 1N hydrochloric acid at pH l.5 to
give 0.22 g of the title compound, rnp >300°.
In a sinnilar manner the following compounds were
prepared:
1-cyclopropyl-6-fluoro-1,4-dihydro-?-(5-methyl-
2,5-diazabicyclo[2.2.1)hept-2-yl)-4-oxo-1,8-naphthyri-
dine-3-carboxylic acid monohydrochloride (b),
mp ~ 310°C dE:c. ,
1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(5-
methyl-2,5-d~.azabi~.~yclo(2.2.1)hept-2-yl)-4-oxo-3-
quinolinecarboxylic acid monohydrochloride (c),
mp 297-29~'C dec., and
1-ethyl-~6,8-difluoro-7-(5-methyl-2,5-diaza-
b icyc to [ 2. 2. 7. ) hept~-2-yl ) -4-oxo-3-quinolinecarboxyl is
acid, hydrochloride (d), mp > 300°C.
i34069~
-41-
EXAMPLE 11
1-Ethyl-7-(5-ethyl-2,5-diazabicyclo[2.2.2]-
oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridin~e-3-carboxylic acid, hydroiodide
A solution of 0.35 g (1.0 mmole) of 7-(2,5-
d iazabicyclo [2. 2.2] oct-2-yl )-1-ethyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
0.32 ml (4.0 mmole) of ethyl iodide, 0.56 ml
(4.0 mmole) triethylamine and 10 ml of N, N-dimethyl-
formamide waa heated at 100° for 1? hours. The
reaction mixiture was evaporated to dryness and the
residue was atirred with 25 ml of 1N sodium hydroxide
f or one hour. The solution was neutralized to pH7
with 1N hydrochloric acid, filtered and evaporated the
filtrate to dryness. The residue was recrystallized
from ethanol to give 0.29 g of the title compound,
mp > 300° .
In the same manner the following compounds are
prepared:
1-ethyl--7-[5-ethyl-2,5-diazabicyclo[2.2.1]-
hept-2-yl] -6" 8-dif:luoro-1, 4-dihydro-4-oxo-3-
quinolinecarboxylic acid, hydrochloride, mp 240-
250°C dec (b;l, and 1-ethyl-7-[5-(1-met.hylethyl)-2,5-
d iazabicyclo ~[2. 2) 1;] hept-2-yl ] 6, 8-difluoro-1, 4-
dihydro-4-oxo-3-qu:inolinecarboxylic acid,
hydrochloride', (c) .
EXAMPLE 12
1-Cyc lopro~yl.-6-f luoro-1, 4-d ihyd ro-7- [ 5- ( 2-hyd roxy-
ethyl)-2,5-di.azabicvclo(2.2.2)oct-2-yl)-4-oxo-1,8-
naphthyridinE~-3-carboxylic acid, monohvdrobromide
A solution of 0.77 g (2.0 mmol) of 7-(2,5-
d iazabicyc to I.' . 2 ( 21 oct-2-yI ) -1-cyc lopropyl-6-
f luoro-1, 4-di.hydro--4-oxo-1, 8-naphthyridine-3-
carboxylic a<:id, 0.70 ml (8.0 mmol) of 2-bromo-
ethanol, 1.3C1 ml (8.0 mmol) of triethylamine, and
4340695
-42-
20 ml of DMF was heated at 100°C for 18 hours.
The reaction solution was evaporated to dryness and
the residue was triturated ethanol. The solid was
collected by filtration to give 0.61 g of the title
product, mp 290°C dec (a).
In the same manner the following compound was
prepared:
1-ethyl-6,8-difluoro-1,4-dihydro-7-[5-(2-hydroxy-
a thyl)-2,5-diazabicyclo[2.2.1]kept-2-yl]-4-oxo-3-
quinolinecarboxylic acid, monohydrobromide (b), mp
242-245°C dec.
EXAMPLE 13
1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(5-
(phenylmethy:l)-2,5-diazabicyclo(2.2,1)hept-2-yll-
3-quinolinecarboxylic acid
A solution of 0,54 g (2.0 mmol) of 1-ethyl-
6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid, 0.77 g (2.2 mmol) of 5-(phenylmethyl)-
2,5-diazabictclo (2.2.1) heptane dihydrobromide,
(P. S. Portoc3hese and A. A. Mikhail, J. Org. Chem. 31,
1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo-
(5.4.0)undec'7-ene, and 20 ml of acetonitrile was
heated under reflu:x for two hours and stirred at room
temperature :Eor two days. The mixture was filtered
and the solic9 was 'washed with methanol to give 0.44 g
of the title compound, mp 195-198°C.
EXAMPLE 14
1-Cyclopropy:L-7-( 1, 4-diazabicvclo [3. 2.1] oct-4-yl-6-
fluoro-4-oxo-1,~4-dih dy ra-1,8-naphthyridine-3-carboxr~lic
acid
A suspension ~of,2.67 g (7.85 mmol) 1-cyclopropyl-
7-ethanesulfonyl-6-fluoro-4-oxo-1,4-dihydro-1,8-
naphthyridinc~-3-carboxylic acid and 1.58 g (8.54 mmol)
' ~3~i~~i~~
- . ~..
-43-
1, 4-diazabicyclo[3,.2. 1]octane dihydrochloride (P. A.
Strum, et al,, J. Med. Chem. , 20 1333 (1977) ] in
40 ml acetonitrile was treated at 0°C with 3.86 g
(25.4 mmol) JL,8-diazabicyclo[5.4.0]undec-7-ene and the
resulting solution stirred 18 hours at room tempera-
ture. Filtration of the ~ precipitate afforded 1. Q4 g
of the title compound, mp 276-278°C with decomposition.
EXAMPLE 15
1-Ethyl-7-(1,4-diazabicyclo[3.2:1]oct-4 yI)-6-
fluoro-4--oxo-~1, 4-dihydro-1, 8-na~hthyridine-3-
carboxylic ac: id
A suspension of 2.06 g (6.213 mmol) t.-ethyl-'~'-
ethanesulfonyl-6-fl.uoro-4-oxo-1, 4-dihydro-1, 8-nap~-
thyr id ine-3-carboxyl is ac id and 1. 29 g ( 6. 97 mmol
1, 4-diazabicyclo[3.. 2. 1] octane dihydrochloride in
30 ml acetoni.trile was treated with 3.10 g
(20.4 mmol) 1.,8-diazabicyclo[5.4.0]undec-7-ene.
The resulting solut:icn was stirred overnight~and
the precipitate which formed was filtered to
afford 0.40 g of tree title compound, mp 228-229°C.
EXAMPLE 16
7-(1,4-Diazabicyclo[3.2.1]oct-4-yl)-1-ethyl-6,8- .
difluoro-1, 4-~dihydz-o-4-oxo-3-quinolinecarboxylic acid
To a solution of 0.81 g (3 mmole) 1-ethyl-6,7t8-
trifluoro-4-oxo-1,4-dihydro-3-~uinolinecar5oxyii.c acid
and 0.46 g (3 mmole~) 1, 8-diazabicyclo[5.4.0]undec-
7-ene in 10 m.l acet:onitrile was added 0.37 g
( 3. 3 mmole) l, 4-diazabicyclo ( 3. 2. 1] octane and the
mixture stirred at reflux 5-1/2 hours. After standing
overnight at room temperature a yellowish solid was
filtered, washed with acetoni~rile and ether and dried
in vacuo to afford 0.22 g product, mp decomposed above
233°C.
134469
-44-
EXA.'~PLE 17
1-Cycloprop~L-7-(1, 4-diazabicvclo[ 3. 2.1] oct-4-
yl ) -6, 8-d ifluoro-1, 4-dihyd ro-4roxo-3-qu inol ine-
carboxyl is ac: id
A mixture of 1.14 g (4 mmol) 1-cyclopropyl-
6, 7, 8-trifluoro-4-oxo-1, 4-dihydro-3-quinoline
c arboxyl is ac: id , 0. 62 g ( 5 . 5 mmol ) l, 4-d iazab icyclo
[3.2.1joctanE: and 0.40 g (4 mmol) 1,8-diazabicyclo
[5.4.0]undec--7-ene in 20 ml acetonitrile was refluxed
6. 5 hours . Af ter cool ing to room temperature the
solid product. was. filtered, suspended in IO ial. hot
a thanol, cooT.ed, and filtered to afford 0. 55 g of
1-cyc iopL~opyl.-7-~ 1, 4-diazabicyclo [ 3. 2. lj octan-4 yl ) -
6 , 8-d i fluo ro--1, 4-d ihyd ro-4-oxo-3-qu inol inecarboxyl is
acid, mp 280°C (dec).
E:tAMPLE 18
1-Ethyl-6, 8-c~ifluoro-1, 4-dihydro-7-( 8-methyl-3, 8-
d iazab icycl o [ 3 . 2. 1 ] oc t- 2-yl ) -4-oxo-3-qu inoi ine-
carboxyl is ac: id ( a;l
A mixture of 1.40 g (5.0 mmole) of 1-ethyl-
6, 7, 8-trifluoro-I, 4-dihydro-4-oxo-3-quinoline-
carboxylic ac: id, 2»0 g (8 mmole) of 8-methyl-3,
8-diazabicycl.o[3. 2» 1] octane dihydrochloride
[P. A. Sturm et al», J. pled. Chem., 17, 481 (1974)j,
2.0 ml (13.3 mmole;l of 1, 8-diazobicyclo[5. 4.0]
undec-7-ene, and 75 ml of acetonitrile was heated
under reflux for 1..5 hr and then stirred at room
temperature f:or 22 hours. The reaction mixture was
evaporated to dryness and the residue was
recrystallizerd frorn 2-propanol to give 0.84 g of the
title compound, mp 184-187°C.
In the ;game manner, the following compounds are
prepared from 8-mei_hyl-3,8-diazabicyclo[3.2.1]octane
d ihydrochlori.de:
~~4oso~
-45-
1-cyclopropy:L-6,8-difluoro-1,4-dihydro-7-(8-methyl-
3, 8-diazabicyclo[ 3. 2. 1] oct-2-yl j-4-oxo-3-quinoline-
c arboxyl is a<: id ( b ) , and
1-cyclopropy):-6-fluoro-1, 4-dihydro-7-(8-methyl-3, 8-
diazabicyclo![3.2.1]oct-2-yl)-4-oxo-1,8-naphthyridi.ne-
3 -carboxyl is ac id ( c ) .
EXAMPLE 19
1-Ethyl-6-fluoro-1, 4-dihydro-7-(3-methyl-3, 8-di.aza-
bicyclo [ 3. 2. :L] oct-2-yl ) -4-oxo-1, 8-naphthyr id ine-3-
carbox 1 is ac: id , h~r~d rochloride .( a )
A mixture of 0. 54 g ( 2 . 0 mmol ) of 7-chloro-1-
ethyl-6-fluoro-1, 4-dihydro-4roxo-1, 8-naphthyridine- _
3 -carboxyl is ac id , 0. 50 g ( 2 . 5 mmol ) of 3-me thyl.-3 , 8-
d iazab icyclo [ 3 . 2. 1] oc tane d ihyd rochloride jP. A. Sturm,
et al, J. Med. Chern., 17, 481 (1974) ] , 0.75 ml
( 5. 0 ml) 1, 8--diazabicyclo[ 5. 4. 0] undec-7-ene and 20 ml
of acetonitri:le was heated under reflux for 1.5 hours
and stirred overniciht at room temperature. The
reaction mixture was filtered and the solid washed'
with ethanol to give 0.46 g of the title compound,
mp > 310° .
In the same manner, the following compounds are
prepared from 3-met:hyl-3, 8-diazabicyclo [3. 2. i]octane
d ihyd rochlori.de and the appropr is to qu inol ine or
naphthyridinEr intex.~.nediate:
1-cyclopropyl-6, 8-~iifluoro-1, 4-dihydro-7-(3-methyl-
3, 8-diazabicyclo[3. 2.1]act-2-yl)-4-oxo-3-c~uinoline-
c arboxyl is ac: id ( b ) , and
1-cyclopropyl-5-fluoro-7-(3-methyl-3,8-diazabicyclo
[3.2.1]oct-2-~yl)-1,4-dihydro-4-oxo-1,S-naphthyridine-
3 -carboxyl is ac id ( c ) .
1340695
-46-
EXAMPLE 20
7-( 3-(Exo-am:ino)-8-azabicyclo [ 3. 2. 1) oct-8-yl ] -1-ethyl-
6-fluoro-1, 4~-dihydro-4-oxo-1, 8-naphthyridine-3-
carboxylic acid, hydrochloride
~ A solution of 0.81 g (3.0 mmole) of 7-chloro-I-
a thyl-6-fluoro-1, 4-dihyd ro-4-oxo-l, 8-naphthyr id ine-3-
carboxylic ac: id, 1.0 g (5 mole) of 3-(exo-amino)-8-
azabicyclo[3..2.1]octane, dihydrochloride, i.35 ml
(9.0 mole) oiE 1,8-diazabicyclo[5.4.0]under-T-ene, and
30 ml of acetonitrile was heated under reflux for two
hours and stirred .at room temperature for 19-hours.
The reaction mixture was filtered and the solid
was dissolved in 20 ml of 0.5 N sodium hydroxide.
The solution was acidified to pH 8 and filtered and the
f il trate was further ac id if ied to pH 2. The sol id was
collected by filtration to give 0.35 g of the title
Compound, mp 300°.
EXAviPLE 21
7-[3-Exo-amino)-8-azabicy l0[3.2.1]oct-8-y11-1-ethyl-
6,8-difluoro--1,4-d:ihydro-4-oxo-3-~uinolinecarboxylic
ac id
A mixture of 0. 27 g (1 mmole) of 1-ethyl-6, 7, 8-
trifluoro-1,4-dihydro-4=oxo-3-quinolinecarboxylic acid,
0.22g (l.l mmole) of 3-(exo-amino)-8-azabicyclo[3.2.1]
octane dihydrochloride, 0.45 ml (3.0 mmole) of I,8-
d iazab icyclo [ S. 4. 0] under-7-ene and 10 ml of aceto-
nitrile was heated at reflux for 18 hours. After
cooling to room temperature, a small amount of solid
was removed t>y filtration and washed with ethanol.
The combined filtrates were concentrated to 10 ml and
refrigerated. The resulting solid was filtered,
washed with ethanol and dried to give 0.14 g of the
title compound, mp 220-225°C.
1340695
-47-
EXAMPLE 22
7-[3-Endo-amino-8-azabicyclo(3.2.1)oct-8-ylj-1-a thvl-
6-fluoro-1, 4-dihydro-4-oxo-1; 8-naphthyridine-3-
carboxylic acid (a)
A solution of 0.81 g (3.0 mmol) of 7-chloro-1-
ethyl-6-fluoro-1, 4-dihydro-4roxo-1, 8-naphthyridine-
3-carboxyl is ac id, 0. 66 g ( 3 . 3 mmol ) of 3-endo
amino-8-azabicyclo[3.2.ljoctane dihydrochloride,
1.35 ml (9.0 mmol) of 1,8-diazabicyclo[5.4.Ojundec-
7-ene, and 30 ml of acetonitrile was heated under
reflux for two hours and stirred at room temperature
for three days. The solid was collected by
f filtration; dissolved with 35 ml of dilute ammonium
hydroxide, faltered, and the solution was concentrated
until the product precipitated. The title compound
was filtered to give 0.40 g, mp 255-259°C.
In a similar manner, the following compounds
were prepared
7- [3-Endo-amino-8-azab icyclo( 3 . 2.1 ) oct-8-yl ] -'
2 0 1-a thyl-6 , 8-c9 i fl uo ro-1, 4-d ihyd ro-4 roxo-3-~u inol fine-
carboxyl is ac: id (b) , mp 208-210°C,
7-[3-Enc9o-amino-8-azabicyclo( 3. 2.1)oct-8-ylj -
1-cyclopropyl!.-6-fluoro-l, 4-dihydro-4-oxo-l, 8-
naphthyr id inc:-3-carboxyl is ac id ( c ) , mp 238°C, and
7-[3-Exo amino-8-azabicyclo(3.2.1)oct-8 ylj-
1-cyclopropyl.-6-fluoro-l, 4-dihydro-4-oxo-l, 8-
naphthyridine:-3-carboxylic acid (d), mp 215-220°C.
EXAMPLE 23
7- [ 3-Exo( acetyl amino) -8-azab ic~lo [ 3 . 2. 1 J oc t-8-yl j -1-
ethyl-6-fluoro-1, 4~-dihydro-4roxo-3-quinolinecart~oxyl is
ac id
A mixtursa of 1,.00 g (3.8 mmole) of 1-ethyl-6,7-
d ifluoro-I, 4--dihydro-4roxo-3--quinol inecarboxyl is
134069
-48-
acid, 0.8 g (3.8 ru-nole) of 3-exo(acetylamino)-8-aza-
bicyclo [3.2.1) octane hydrochloride, 1.14 ml
( 7. 6 mmole) of 1, 8-diazabicyclo[ 5. 4. 0] undec-7-ene,
and 50 ml at acetonitrile was heated under reflux for
18 hours. After cooling to room temperature, the
reaction mixture was filtered and the solid was washed
with acetonitrile and methanol to yield 0.55 g of the
title compound, m.p. > 300°.
EXAMPLE 24
7-[3-Exo(acetylamino)-8-azabicyclo[3.2.1]oct-8-yI]-
1-ethyl-6-fluoro-1, 4-dihydro-4roxo-1, 8-naphthyridine-
3-carboxyl is ac id
A mixture of 0.95 g (3.5 mmole) of 7-chloro-1-
ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine,
0.72 g (3.5 mmole) of 3-exo (acetyl amino)-8-azabicyclo
[3.2.1]octane hydrochloride, 1.05 ml (7.0 mmole) of
1,8-diazabicyclo[5.4.0]undec-7-ene, and 30 ml of
acetonitrile was heated under reflux for 2 hours:
After cooling to room temperature, the reaction
mixture was filtered and the solid was washed with
acetonitrile and methanol to yield 0.99 g of the
t i tle compound, mp > 300° .
EXAMPLE 25
7-[3-Endo( acet~la~-nino)-8-azabicycl of 3. ?. 1] oct-8-
yl] -1-ethyl-6-fluoro-1, 4-dihydro-~-o:co~-'-~uinol ine-
carboxyl is ac id
A mixture of 1.31 g (~.0 mmol) of 1-ethyl-6,7-
d ifluoro-1, 4-dihydro-4-oxo-3--quinol ir~ecaraoxyl is
acid, 1.23 g (6.0 mmol) of 3-endo(acetylamino)-8--
azabicyclo[3.2.1]octane hydrochloride, 1. SO ml
( i0 mmol) of ? ( 8-diazak~icyclo[S. 4. 0]undac-'-ene,
ml of acetonitrile and 10 .nl of diuiethyl
434~s95
-4 9-
formamide was heated under reflux for 19 hours.
Af ter cool ing to room temperature, the reaction
mixture was filtered and the solid was washed with
acetonitr ile and ethanol to give 1. 04 g of the
title compound, mp > 300°.
EYA~IPLE 26
7-[3-Endo( acetyl amino)-8-aza'aicyclo[3. 2. ljoct-8-
yl] -1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naph-
thyr id ine-3-carboxyl is ac id
A mixture of 0, 54 g (2. 0 mmol) of 7-chloro-1-
ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-napthyridine-
3-carboxyl is ac id, 0. 41 g ( 2. 0 mmol ) of 3-endo
(acetylamino)-8-azabicyclo[3.2.1]octane, 0.6 ml
(4.0 mmol) of 1,8-diazabicyclo(5.4.0]undec-7-ene,
and 50 ml of acetonitrile was heated under reflux
for S hours. After cooling to room temperature,
the reaction mixture was filtered and the solid was
washed with acetonitrile and water to give 0.37 g
of the title compound, mp > 300°.
E:SAMPLE 27
7-[5-[ (4-ami:nophenyl) methyl] 2-, 5-diazabicvclo-
(2. 2. 1] kept-2-yl]= 1-cycloprooyl-6, 8-difluoro-1, 4-
dihydo-4-oxo~-3-ruinol inecaraoxyi is acid
A solution of :L.52 g (4.0 mmol) oz 7-(2,5-
2 5 d iazab icyclo [ 2 . 2. 1] nept-2-yl ) -1-cyclonropyL-6, 8-
d iiluoro-1, S-dihyd ro-4-oxo-3-qu inol inecarboxyl is
acid, i.3 g (0.0 mmol) of 1-(bromometnyl)-4-
nitrobenzene, 1.12 ml (8.0 rnmol) of trietilyla:nizze and
40 ml of N-V-di:netilylfo~amide was heated at 100° for
18 hours. The solution was eva~rateci to :3rynes5 an~i
the residue was treated with water ar.~i fi~.tered to
. . '
~34os9~
-50_
give 1.61 g of 1-cyclopropyl-6,8-diLluoro-1,4-dihydra-
7-[5-[(4-nit,rophenyl)methyl]-2,5-diazabicyclo[2.2.1]-
hept-2-yl]-4~-oxo-a-quinolinecarboxylic acid,
mp 177-182°.
A solution of 1.33 g (2.54 mmol) of the above
compound, 0.05 g 5$ Pd/C and 100 1 of acetic acid
was hydrogenated until the requisite amount of
hydrogen uptake was observed. The reaction mixture
was filtered and the filtrate was evaporated. The
residue was dissolved with water and Na2C03 solution
was added to~ pH 7Ø The solid was collected by
filtration to yield 0.37 g of the title compound.
EXAMPLE: 28
In a similar manner to Example 27, 7-(2,5-
diazabicyclo[2.2.2]oct-2-yl)-1-cyclopropyl-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic
was alkylated with, 1-(bromomethyl)-4-nitrobenzene and
the product was hydrogenated to give ?-[~-[(4-
aminophenyl)methyl]-2,S-diazabicyclo[2.2.2]oct-2-
yl]-1-cyclopropyl-~6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid.
